PROJECT SUMMARY/ABSTRACT Peptide receptor radionuclide therapy (PRRT) with [177Lu]DOTATATE improves quality of life and survival in patients with advanced neuroendocrine tumors; however objective tumor regression is infrequent and complete responses are exceedingly rare. On the other hand, exciting-emerging evidence suggests that PRRT with alpha-emitters has the potential to extend PRRT to tumor regression and even complete response. In this study we propose to develop a new theranostic pair using [203Pb]PSC-TOC (imaging) / [212Pb]PSC-TOC (alpha emitter) for image-guided dosimetry based personalized therapy for neuroendocrine tumors. In Specific Aim 1 of the proposal, we will optimize the radiolabeling and production of [203/212Pb]PSC-TOC to prepare for its use in clinical trials and perform a preclinical dose escalation trial in immune-competent mice to investigate drug toxicity and the relation of toxicity with radiation dose (using residence time as a surrogate) to the organs. The accurate measurement of radiation dose from alpha-emitters is challenging due to dependence of the dose on the distribution of the radiopharmaceutical at cellular and subcellular level. In Specific Aim 2, we propose to develop a surrogate for organ dosimetry based on the residence time of the radiopharmaceutical in a human imaging trial with [203Pb]PSC-TOC, This methodology requires serial imaging over multiple days. We will then extend the dosimetry methodology to develop a predictive model to identify the best single imaging time point that predicts kidney accumulation, similar to our previous work with 90Y-DOTATOC, for translation of the dosimetry procedure into the clinical practice. Finally in Specific Aim 3 we will conduct a Phase 1 dose escalation trial of personalized dosimetry-guided therapy with [212Pb]PSC-TOC in patients with advanced stage NETs who have progressed or are refractory to conventional PRRT with beta emitters. The dose escalation paradigm will be based on escalating critical organ dose limits (using residence time as surrogate for dosimetry). The primary objective of the Phase 1 clinical trial will be the identification of the maximum safe kidney dose surrogate from treatment with [212Pb]PSC-TOC that should be used for a subsequent Phase 2 efficacy trial with the agent. As a secondary objective we will assess objective tumor response to PRRT with [212Pb]PSC-TOC. .